Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
  • A61K8/36—Carboxylic acids; Salts or anhydrides thereof
  • A61K8/368—Carboxylic acids; Salts or anhydrides thereof with carboxyl groups directly bound to carbon atoms of aromatic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
  • A61K31/05—Phenols
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/365—Lactones
  • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
  • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
  • A61K36/18—Magnoliophyta (angiosperms)
  • A61K36/185—Magnoliopsida (dicotyledons)
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
  • A61K8/34—Alcohols
  • A61K8/347—Phenols
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
  • A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
  • A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
  • A61K8/498—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom having 6-membered rings or their condensed derivatives, e.g. coumarin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/60—Sugars; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
  • A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
  • A61K8/9783—Angiosperms [Magnoliophyta]
  • A61K8/9789—Magnoliopsida [dicotyledons]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
  • A61Q17/04—Topical preparations for affording protection against sunlight or other radiation; Topical sun tanning preparations
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q19/00—Preparations for care of the skin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q19/00—Preparations for care of the skin
  • A61Q19/007—Preparations for dry skin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q19/00—Preparations for care of the skin
  • A61Q19/08—Anti-ageing preparations

Definitions

• the present invention relates to a compound, its salts and its derivatives, said compound being chosen from gallic acid, hexahydroxydiphenic acid, ellagic acid and derivatives of these acids and in particular gallotannins and ellagitannins, as well as its cosmetic and pharmaceutical applications.
• the compounds of the invention have an efficacy for restoring the barrier function of human or animal organs, whether external such as the epidermis or internal as those of the digestive tract, allowing strengthen the protection of the organs against the aggressions that they undergo, for example environmental aggressions concerning the epidermis or lesions associated with a pathological state.
• Such properties are particularly useful for preventing or treating skin conditions such as acne, atopic dermatitis, psoriasis, eczema, dryness of the skin with atopic tendency, redness, but also for preserving skins. young people against natural or premature aging as well as aged skin, as well as to prevent or treat diseases of an internal organ or the consequences of these pathologies, such as Crohn's disease.
• the stratum corneum is the most superficial part of the skin and represents the culmination of the keratinocyte differentiation process.
• keratinocytes from the basal layer undergo a series of metabolic and structural changes throughout their migration to the surface of the skin.
• the last stage is their transformation into corneocytes whose accumulation in a cohesive structure constitutes the stratum corneum which provides the barrier function.
• proteins intervene.
• TGK glutaminase family catalyzes the establishment of covalent peptide bonds of the s ( ⁇ -glutamyl) -lysine type between various protein precursors which form the stratum corneum and confers on it this ability to protect the skin against external aggressions and limit the diffusion of water from the inside.
• Transglutaminase forms generally insoluble protein polymers. These biological polymers are essential for the body to create barriers and stable structures.
• the present invention aims precisely to offer new compositions capable of stimulating the factors involved in differentiation, called pro-differentiating agents such as TGK, thus making it possible to improve the conditions of the skin, superficial body growths, as well as mucous membranes, healthy or injured, and thus to reinforce their functions, but also those of the wall of internal organs.
• pro-differentiating agents such as TGK
• Crohn's disease is a chronic inflammatory disease that can reach the entire digestive tract. It develops most often in the intestines resulting in an alteration of the wall by ulcerations and cracks in the wall resulting in the loss of its barrier function.
• Dermatoses are conditions of the skin and mucous membranes, which are characterized by unsightly manifestations such as redness and desquamation plaques.
• Several pathologies are grouped under the denomination of dermatoses. There may be mentioned, as non-limiting examples, eczema, atopic dermatitis, psoriasis, seborrheic dermatitis or acne. Dermatosis causes alterations in the barrier function of the epidermis resulting in permeability of the skin, dryness of the skin and general deterioration of the protective functions of the skin vis-à-vis the external environment.
• the invention relates to the applications of a compound, a salt of this compound, a derivative of this compound or a salt thereof, said compound being chosen from gallic acid, its hydrolyzable polymers, and gallic acid, hexahydroxydiphenic acid, its hydrolyzable polymers to hexahydroxydiphenic acid, ellagic acid, its hydrolyzable polymers to ellagic acid, gallotannins and ellagitannins.
• the gallotannins include, but are not limited to, tannic acid and 1,2,3,4,6-penta-O-galloyl-beta-D-glucopyranose.
• vescalagin castalagine, casuarinine, stachyurine, salicarinin A (vescalagine-stachyurine dimer), salicarinin B (vescalagin-casuarinine dimer) and salicarininin C (castalagine dimer -casuarinine).
• HHDP Hexahydroxydiphenic acid
• Salicarinin A (vescalagin-stachyurine dimer)
• Salicarinin B (dimer vescalagin-casuarinin)
• Salicarinin C (castalagine-casuarinine dimer)
• a compound derivative undit suitably corresponds to a structure which comprises at least one residue of hexahydroxydiphenic acid (HHDP) and a hydrocarbon chain, aliphatic, saturated, of 6 carbon atoms, said remainder of HHDP being fixed on said chain by through its carboxyl groups.
• Said hydrocarbon chain may optionally be substituted with a group chosen from C1-C6 alkyl groups and C3-C6 cycloalkyl groups, optionally interrupted by at least one or more oxygen atoms and optionally substituted with one or more groups chosen from C1-C6 alkyl groups, C3-C6 cycloalkyl groups, hydroxy group and C1-C6 alkoxyl groups.
• a compound above may have one or more asymmetric center (s).
• the compound may be in an optically active form or in the form of its racemic mixture.
• alkyl denotes a monovalent hydrocarbon radical linear or branched preferably having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, ⁇ -hexyl.
• the alkyl groups may be substituted with one or more hydroxyl groups and / or with one or more alkoxy groups.
• cycloalkyl denotes a cyclic hydrocarbon monovalent radical comprising from 3 to 6 carbon atoms and which may be mono- or poly-cyclic.
• alkoxy groups correspond to the linear or branched alkyl groups defined above connected by via a -O- (ether) linkage. Most preferred is methoxy, ethoxy, n-propyloxy, / 'propyloxy, n-butoxy, s-butoxy, t-butoxy, pentoxy and ⁇ -s-pentoxy.
• the alkoxy groups may be substituted by an alkyl group as defined above or by another alkoxy group.
• Hydrolyzable polymers made of gallic acid and polymers that are hydrolyzable to hexahydroxydiphenic acid include, in particular, polymers which are partially or completely hydrolysed by the skin on its surface or in any one of its layers, it being understood that gallic acid and hexahydroxydiphenic acid, as well as said partially hydrolysed polymers are active.
• Certain compounds of the invention can be obtained from plants by extraction and are therefore easily accessible. They can also be used according to the present invention in the form of plant extracts.
• a compound can be obtained by any method including organic synthesis, or by isolation from a plant source and in particular a plant, such as a plant of the family Lythraceae, the Fagaceae family, Myrtaceae family, Combretaceae family, Eléagnaceae family, Melastomaceae family, Myricaceae family or Rosaceae family.
• these families include the following plant species: Lythrum salicaria L, Quercus sp, Castanea sp, Anogeissus leiocarpus (DC.) Guill.
• the compound may be in salified form, so it extends to any salt of said compound.
• This salt is advantageously acceptable from a cosmetic or pharmaceutical point of view.
• a salt of a compound of the invention may be an acid addition salt, said acid being preferably selected from hydrochloric acid, hydrobromic acid, sulfuric phosphoric acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid and glutaric acid. , fumaric, tartaric, maleic, citric, ascorbic, methane- or ethanesulfonic, and camphoric. It may also be a base addition salt, the latter being preferably chosen from sodium or potassium hydroxide, triethylamine or tert-butylamine.
• the invention relates to the cosmetic applications of a compound or a salt of this compound, as defined above, but also the mixture of compounds and / or salts and / or derivatives thus defined.
• the invention relates to their uses for stimulating or repair the barrier function of the epidermis. More particularly, it aims their use as an active ingredient in a cosmetic composition to stimulate or repair the barrier function of the epidermis.
• the concentration of said compound, salt or derivative or mixtures thereof ranges from 0.001% to 5% by weight relative to the total weight of the composition, preferably 0.01% to 5%, or even 0.05% to 5%, by weight relative to the total weight of the composition.
• the invention further relates to pharmaceutical applications, including veterinary, a compound, salt or derivative as defined above.
• pharmaceutical applications including veterinary, a compound, salt or derivative as defined above.
• it is of particular interest when used in the prevention or treatment of lesions caused in the organ walls by pathologies, such as Crohn's disease, particularly in the intestinal wall. It is also advantageously intended for the prevention or treatment of lesions associated with dermatoses such as atopic dermatitis, eczema, psoriasis, seborrheic dermatitis and acne.
• compositions for preventing or treating lesions caused by pathologies such as Crohn's disease and containing an effective amount of a compound of the invention, or a salt thereof, a derivative of this compound or a salt of a derivative, as defined above, and a pharmaceutically acceptable carrier.
• Undit salt is compatible with a pharmaceutical use and preferably an addition salt of hydrochloric acid, hydrobromic acid, sulfuric phosphoric acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, methane or ethanesulfonic or camphoric, a base addition salt selected from sodium or potassium hydroxide, triethylamine or tert-butylamine.
• the compound, its salt or the composition or the composition thereof is intended for oral administration.
• a pharmaceutical composition of the invention also advantageously meets the following characteristics, considered alone or in combination.
• the compound is in powder form, in the form supported by absorption on an organic polymer powder such as bentonite or talc, or in encapsulated form;
• the compound is encapsulated in microspheres, liposomes, glycospheres, chylomicrons, macro-, micro- or nanoparticles, or macro-, micro- or nanocapsules;
• the composition contains an active principle that is effective in chronic inflammations, such as an active ingredient chosen from mucopolysaccharides, vitamins, ceramides and vegetable oils;
• composition comprises at least one active agent other than a compound of the invention for exerting at least one complementary or synergistic action.
• the compound, its salt or derivative and mixtures thereof are used in the form of plant extract, without complete purification.
• plant extract means an extract or a mixture of plant extracts from the families listed above. It is more particularly an extract or a mixture of cell extract of these families.
• This cellular material can be obtained by in vitro culture or in vivo.
• in vitro culture is meant all of the techniques known to those skilled in the art that artificially allow the production of a plant or part of a plant.
• the extract may be an extract or a mixture of organ extracts (root, stem, leaf, bark, flower), or even of organ cells, of at least one plant of the abovementioned families, or a undifferentiated cell extract from at least one such plant.
• An extract according to the invention can be obtained by any extraction or purification method known to those skilled in the art. It is possible in particular to mention the solid-liquid extraction processes in alcoholic (in particular methanolic, ethanolic) and aqueous media, as well as in media using solvents such as ketones, esters, ethers, polyols and chlorinated solvents. and mixtures of at least two of the aforementioned solvents, such as hydroalcoholic media.
• an extract is obtained by extraction of a family of aforementioned plants in a hydroalcoholic medium, in particular an aqueous solution of ethanol.
• the concentration of the ethanol preferably ranges from about 20 to about 40% (v / v), more preferably it is about 30% (v / v).
• These extracts can be used as such in liquid or powder form, unpurified or purified.
• the extract is powdered, its drying can be conducted by any technique well known to those skilled in the art.
• the extract can be dried by atomization, evaporation or lyophilization.
• the powder thus obtained can be encapsulated in liposomes or other vectors and supports for better homogeneity of the composition and better diffusion of the active ingredient, especially on the skin.
• the extract is preferably obtained from flowering tops.
• the authors observed that the extracts obtained by hydroalcoholic maceration of the aerial parts of loosestrife show a strong biological activity. This regardless of the percentage of ethanol in the extraction solvent. Similar results are observed in water or ethanol.
• the applications according to the invention extend to the treatment of integuments and mucous membranes.
• dander according to the invention include nails and the hair system, especially the hair.
• Mucous membranes are the covering tissues of the anatomical cavities, which are connected to the skin by natural orifices, such as the mouth, the stomach, the intestine, as well as those of natural external cavities such as the nostrils and the ears.
• the present invention also aims at the cosmetic use of a compound or a salt of said compound, or a mixture of compounds and / or their salts, to protect the skin, integuments and mucous membranes of external agents physical, chemical or biological, and / or to improve and / or enhance the hydration of the skin and / or strengthen the integuments and mucous membranes.
• the invention also relates to a cosmetic treatment method, non-therapeutic, anti-aging of the skin or cosmetic treatment, non-therapeutic, of an aged skin, comprising a step according to which at least one compound, salt or derivative is applied. , or their mixtures as defined above, synthetic or extracted from a plant on the skin. This treatment helps to delay the aging phenomena of the skin, but also to repair an aged skin.
• a compound, salt or derivative, or their mixtures as defined above may be combined with another or other pro-differentiating agents of the skin, such as calcium, vitamin D and their derivatives.
• a composition according to the invention is in the form of capsules, cream, gel, lotion, milk, O / W or W / O emulsion, solution, ointment, body oil, shampoo, soap, stick protector of the lips, stick and pencil for makeup.
• the composition may comprise suitable excipients, such as cellulose esters, or other gelling agents, such as carbopof carboxylic polymer and guar gum, for example.
• the compositions according to the invention have good stability and can be stored for the time necessary for use at temperatures between 0 and 50 ° C., without there being any sedimentation of the compositions. constituents or phase separation.
• a compound, salt or derivative, or their mixtures as defined above is put in place in encapsulation means chosen from the group formed by microspheres, liposomes, glycosphers, chylomicrons, macro-, micro- and nanoparticles, macro-, micro- and nanocapsules.
• a compound, salt or derivative, or their mixtures as defined above is absorbed or adsorbed on powdery organic polymers, talcs, bentonite or other mineral supports powder well known to those skilled in the art.
• a compound, salt or derivative, or their mixtures as defined above constitutes from 0.001% to 5% by weight relative to the total weight of the composition, preferably 0, 01% to 5%, or even 0.05% to 5%.
• a compound, salt or derivative, or their mixtures as defined above is in encapsulated form and constitutes, preferably from 0.05 to 5% by weight relative to the weight total of the composition.
• the subject of the present invention is a cosmetic use of at least one compound, salt or derivative, or their mixtures as defined above, for soothing dry skin with an atopic tendency and / or for improving and / or enhancing hydration. skin.
• it relates to the uses of at least one compound, salt or derivative, or their mixtures as defined above, as an active ingredient in a cosmetic composition intended to be applied to dry skin with an atopic tendency, to the fight against skin aging such as age-related aging and / or photo-aging, the fight against itching and itching, hydration and protection against external aggression related to pollution and stress.
• a compound, salt or derivative, or their mixtures as defined above may be administered topically, but can also be administered orally. It can be used as it is in liquid or powder form, not purified or purified.
• a compound, salt or derivative, or their mixtures as defined above, may, in the compositions according to the invention, be combined with other compounds that complement the effect or even synergize this effect.
• the restorative activity of a compound, salt or derivative, or their mixtures as defined above is particularly advantageous when it is combined with substances having a healing effect such as proteins, hyaluronic acid, acids and the like. amino, or with anti-inflammatory substances, anti-aging, after-sun anti-acne or anti-dermatosis.
• compositions of the invention are particularly suitable for topical application to prevent and / or treat many skin disorders, especially as a repairing agent and / or protector of the skin and the hair system such as the hair, to fight against external aggressions related to pollution, sun, oxidative stress, aging and cutaneous pathologies leading to dysfunction of the homeostasis of the epidermis or hair.
• These cosmetic compositions may also take the form of a lotion or solution in which the derivatives according to the invention are in encapsulated form, for example in microspheres.
• microspheres may, for example, consist of fat, agar and water.
• the active agents may also be incorporated into liposome, glycosphere-type vectors in chylomicrons, macro-, micro-, nanoparticles as well as macro-, micro- and nanocapsules and also be adsorbed onto powdery organic polymers, talcs , bentonites and other mineral supports.
• compositions according to the invention may be mixed with the excipients generally used in cosmetics.
• the cosmetic compositions of the invention may therefore contain additives or adjuvants customary in cosmetology, such as, for example, antibacterial agents or perfumes, but also extraction and / or synthetic lipids, gelling and viscosity polymers, tensio- active ingredients, emulsifiers, hydro- or liposoluble active ingredients, plant extracts, tissue extracts, marine extracts, or synthetic active ingredients.
• a dermocosmetic or pharmaceutical composition of the invention comprises all skincare and skin care products, including sun, protective and tanning products, anti-aging, anti-seborrhoeic, tonic and improving products.
• the appearance of the skin including acne treatment, skin redness treatment, scalp treatment and hair loss.
• compositions of the present invention may also comprise other complementary active agents chosen for their action, for example for sun protection, the anti-wrinkle effect, the antiradical and antioxidant activity, the anti-irritant activity, the cellular nutrition, cellular respiration, cellular hydration and regeneration, anti-seborrhoeic treatments, as well as other active agents having an effect on skin tone and protection of the hair.
• other complementary active agents chosen for their action, for example for sun protection, the anti-wrinkle effect, the antiradical and antioxidant activity, the anti-irritant activity, the cellular nutrition, cellular respiration, cellular hydration and regeneration, anti-seborrhoeic treatments, as well as other active agents having an effect on skin tone and protection of the hair.
• the cosmetic compositions of the present invention are preferably used daily by applying them one or more times daily.
• compositions of the present invention are very well tolerated, they exhibit no phototoxicity and their application to the skin for prolonged periods of time does not imply any systemic effect.
• the invention also relates to the use of a compound, a salt of this compound, a derivative of this compound, a salt of this derivative, or their mixtures as defined above, for the preparation of pharmaceutical compositions having anti-inflammatory and / or dermoprotective activity.
• These compositions are useful for preventing and / or treating in particular dermatological diseases related to seborrheic, acneic, inflammatory and immunological activities.
• FIG. 1 represents the chromatogram of the salicarial extract obtained by semi-preparative HPLC under the conditions described in Example 2, representing the concentration (expressed in absorbance units) of the constituents of a loosestrife extract as a function of retention time (in minutes).
• Figures 2, 3 and 4 show the effects of a salicarial extract and vescalagin on the release of three mediators, MMP-1 (Figure 2), MMP-3 ( Figure 3) and Procollagen 1 ( Figure 4) by skin rebuilt after 9 days in distressed environment.
• FIG. 5 represents the influence of a salicarial extract, EX10MF1046, on the expression of different markers of epidermal differentiation, by keratinocyte cultures in the basal state, evaluated by RT-qPCR.
• FIG. 6 shows the digital images of reconstructed epidermis cut (RHE) treated with a control, a reference and the extract of loosestrife, EX10MF1046, at 20 ⁇ g / ml, and their effects on the expression of markers of epidermal differentiation.
• FIG. 7 represents the influence of the salicarial extract, EX10MF1046, on the expression of different markers of epidermal differentiation, by the cultures of keratinocytes stimulated or not by a mixture of cytokines IL-17, OSM and TNF ⁇ (mix -PSO), evaluated by RT-qPCR.
• FIG. 8 presents the digital images of reconstructed epidermal sections stimulated by a mixture of cytokines IL-17, OSM, TNF ⁇ treated with a control, a reference (JAK inhibitor 1) and the extract of loosestrife, EX10MF1046 at 20 ⁇ g / ml, and their effects on the expression of the KRT10 epidermal differentiation marker.
• FIG. 9 represents the influence of the salicane extract, EX10MF1046, on the expression of various chemokines induced by inflammation, by keratinocyte cultures stimulated or not by a mixture of cytokines IL-17, OSM and TNF ⁇ ( mix- PSO), evaluated by RT-qPCR.
• FIG. 10 represents the influence of the extract of salicarum, EX10MF1046, on the release of IL-8 by reconstructed epidermis (RHE at J13) stimulated by the mixture of cytokines IL-17, OSM and TNF ⁇ (mixed PSO) for 48h, observed in Figure 7.
• Figure 11 shows a diagram of a chronic inflammatory skin loop (eg, psoriasis) illustrating the stage of intervention of the loosestrife extract, EX10MF1046, in this loop.
• a chronic inflammatory skin loop eg, psoriasis
• Example 1 Obtaining extracts of loosestrife [Lythrum salicaria L) comprising a compound of the invention
• Example 2 Isolation of a Compound of the Invention from an Extract of Loosestrife and Characterization
• a first purification step is carried out by solid phase extraction (SPE).
• the support chosen is a C18 grafted silica.
• the extract is deposited in solution in a hydroalcoholic solution containing 20% methanol and 0.5% formic acid. Elution is carried out with the same solvent. The fraction obtained is concentrated by evaporation and then lyophilized.
• a second purification step is performed by semi-preparative HPLC on a Synergi Fusion column (Phenomenex) of dimensions 250x10mm. Elution is provided by a 0.5% formic acid gradient and methanol.
• Gallic acid was identified by comparing the physicochemical characteristics (retention, ultraviolet absorption spectrum and mass spectrum) of the compound present in the extract with those of a commercial sample of gallic acid (Sigma Aldrich - reference 27645) .
• Compound A has a UV absorbance maxima at 269 nm and a monoisotopic molar mass of 170 g / mol. Its retention time under the HPLC conditions used is 6.90 minutes.
• the commercial sample of gallic acid has exactly the same physicochemical characteristics. These elements make it possible to identify compound A as gallic acid.
• Tables 4 and 5 show the chemical shifts of the compound C, in 13C NMR and proton NMR, respectively. All of these chemical shifts identify compound C as being castalagine.
• Culture medium KeratinocyteSFM supplemented with epidermal growth factor (EGF) 0.25 ng / ml, pituitary extract (PE) 25 ⁇ g / ml and gentamycin 25 ⁇ g / ml.
• EGF epidermal growth factor
• PE pituitary extract
• Test medium KeratinocyteSFM supplemented with gentamycin 25 ⁇ g / ml.
• gallic acid vescalagin, castalagine and salicarinin A compounds are tested at the following concentrations:
• Gallic acid 0.0033; 0.01 and 0.03 mg / ml
• Salicarinin A 0.0011; 0.003 and 0.01 mg / ml
• the test medium is removed and the cells are rinsed, fixed and permeabilized.
• Cells are labeled with primary antibodies against the proteins of interest (TGK). These antibodies were revealed by a secondary antibody coupled with a fluorochrome (GAMAlexa 488).
• GAMAlexa 488 a secondary antibody coupled with a fluorochrome
• the nuclei of the cells are stained with Hoechst 33258 (bisbenzimide).
• the images are acquired with a high-resolution imaging system, I NCell Analyzer TM 1000 (GE Healthcare). For each well, 5 entries of scanned images are made. The markings are quantified by measuring the fluorescence intensity of the proteins referenced to the number of nuclei identified by the Hoechst (digital data integration by the Developer Toolbox 1.5 software, GE Healthcare).
• Table 6 illustrates the expression level of TGK via fluorescent labeling of NHEKs for different concentrations of vescalagin, castalagine and salicarinin A.
• Table 7 illustrates the expression level of TGK via the fluorescent labeling of N HEKs for different concentrations of gallic acid.
• Human skin reconstructed from a culture of keratinocytes seeded on a lattice of collagen containing fibroblasts.
• the keratinocytes are cultured at 37 ° C., 5% CO 2 , at the air-liquid interface in one of the following media:
• Complete culture medium Epilife and complements (without IGF-1) + CaCl 2 1.5 mM + bovine insulin 5 ⁇ g / ml + vitamin C 50 ⁇ g / ml + KGF (keratinocyte growth factor) 3 ng / ml, or
• Depleted culture medium Epilife and complements (without IGF-1 and without hydrocortisone) + 1.5 mM CaCl 2 + vitamin C (50 ⁇ g / ml).
• a dermal compartment composed of fibroblasts in a collagen matrix
• a basal layer (a layer of palisade cells)
• a thorny layer (4 to 5 layers of cells)
• a granular layer (a layer of cells with keratohyaline grains), and A stratum corneum (dead cells anucleate).
• a basal layer (a layer of palisade cells)
• a basal layer (a layer of palisade cells)
• the expression profiles of the selected genes are very different between the reconstructed skins cultured in complete medium and those grown in depleted medium.
• the skin reconstructed in a depleted environment shows a very strong increase in the expression of markers of matrix degradation (MMP1, MMP3, TFPI2), markers of inflammation (PTGS2, IL1B), and markers of the differentiation of the keratinocytes (FLG, TGM1, CDSN).
• MMP1, MMP3, TFPI2 markers of inflammation
• PTGS2, IL1B markers of the differentiation of the keratinocytes
• FLG, TGM1, CDSN markers of the differentiation of the keratinocytes
• Vescalagin systemically tested at 30 ⁇ g / ml and 60 ⁇ g / ml in deformed environment partially compensated, in a dose-dependent manner, the effect of the deficient medium including:
• the systemic treatment with the loosestrife extract at 30 ⁇ g / ml and 60 ⁇ g / ml of the skin reconstructed in de-cultured culture medium induces a significant and significant decrease in the release of MMP-1 and MMP-3. At the same time, it significantly stimulates the release of procollagen I.
• Culture medium KeratinocyteSFM supplemented with epidermal growth factor (EGF) 0.25 ng / ml, pituitary extract (PE) 25 ⁇ g / ml and gentamycin 25 ⁇ g / ml.
• EGF epidermal growth factor
• PE pituitary extract
• Test medium KeratinocyteSFM supplemented with gentamycin 25 ⁇ g / ml.
• EX1M extracts F1046, EX2MF1046, EX3MF1046, EX4M F1046 and EX13MF1046 of Example 1 are tested at the following concentrations:
• the test medium is removed and the cells are rinsed, fixed and permeabilized.
• the cells are labeled with the primary antibodies directed against the proteins of interest (TGK, filaggrin and KRT10). These antibodies were revealed by a secondary antibody coupled to a fluorochrome (GAMAlexa 488).
• GAMAlexa 488 a secondary antibody coupled to a fluorochrome
• the nuclei of the cells are stained with Hoechst 33258 (bisbenzimide).
• the images are acquired with a high-resolution imaging system, I NCell Analyzer TM 1000 (GE Healthcare). For each well, 5 entries of scanned images are made.
• the labels are quantified by measuring the fluorescence intensity of the proteins relative to the number of nuclei identified by the Hoechst (digital data integration by the software Developer Toolbox 1.5, GE Healthcare).
• test medium was removed and the cells were rinsed and frozen at -80 ° C.
• RNAs messenger RNAs extracted from the cell mats of each treatment (the replicates were pooled before the extraction of the RNA).
• the RNA extraction steps, reverse transcription, primers and PCR conditions have been previously described 1 "3 .
• Extract EX3MF1046 proves to be the most active under these conditions.
• Table 11 illustrates the expression level of TGK via the fluorescent markagi NHEK for different concentration of EX3MF1046 extract.
• TGK expression is given as fluorescence intensity / number of cells (AU)
• Table 12 provides an assessment of the level of expression of the above three markers via fluorescent labeling of NHEKs.
• the analysis was extended to other protein markers of epidermal differentiation, namely, loricin, involucrine and keratin 1 (KRT1).
• EX10MF1046 The influence of EX10MF1046 at 20 ⁇ g / ml is studied on the expression of the transcripts of the various markers above by the keratinocyte cultures in the basal state.
• the treatments are 48 h, the analysis is performed by RT-qPCR.
• the results are given in% of untreated controls after randomization of the relative expressions with respect to the GAPDH household gene. They are represented in FIG.
• the RT-qPCR analyzes show a very clear overexpression of all the markers of differentiation in the presence of the extract; stimulations were strong (stimulation from a factor of 4 to several tens of times depending on the markers) and all higher than those obtained with calcium, with the exception of the involucrine marker.
• the RHEs are cultured at 37 ° C, 5% C0 2 , at the air-liquid interface, in Epilife + 1.5 mM calcium medium and supplements, without vitamin C.
• the reference for studies of pro-differentiating effects is vitamin C (50 ⁇ g / ml).
• Extracts tested EX10MF1046 extract of Example 1 was tested at 20 ⁇ g / ml, in the medium of culture of the RHE.
• the RHEs are placed at the air-liquid interface (OJ) and cultured for 7 days in the presence or absence (control) of the extract EX10M F1046 or vitamin C (reference).
• the epidermis are rinsed and then fixed in a solution of formaldehyde.
• the fixed tissues are dehydrated by successive and increasing ethanol baths then included in paraffin "Paraplast".
• Cross sections are made with a microtome (thickness 5 ⁇ ) and then kept at room temperature until the markings are made.
• the sections are deparaffinized and the antigenic sites are unmasked in a solution of citrate buffer pH6 (DAKO, S1700). After washing in PBS-T, the sections are incubated with a 3% hydrogen peroxide solution for 5 minutes. After washing, the sections are then incubated at room temperature for 1 hour with the primary antibody (anti-TGK, SC-25786, anti-KRTIO, SC-23877, anti-filaggrin, SC-66192, all from Santa Cruz Biotech). After washing, labeling is revealed with a streptavidin-peroxidase detection kit (DAKO, K0690) coupled to the AEC chromogen (DAKO, K346111).
• DAKO streptavidin-peroxidase detection kit
• the sections are mounted between the slide and the lamella in Glycergel aqueous medium (DAKO, C056330). The sections are observed using a NI KON E400 microscope. Digital images are recorded with an NI KON DS-Ril camera and NIS-Elements 3.10 software.
• transition to the air-liquid interface leads, in the optimal conditions of epidermal reconstruction, to a very strong differentiation that is very difficult to overstimulate. Also it is appropriate to put in non-optimal conditions or slightly deficient to see the effect of products stimulating differentiation.
• the extract EX10MF1046 shows a clear compensation and strong stimulation of the expression of KRT10, filaggrin and TGK.
• Example 7 Protective effects of loosestrife extracts on cutaneous lesions induced by inflammation (psoriasis, dermatitis) of the epidermis; evaluation in reconstructed epidermis (RHE)
• NHEKs Reconstructed cells and epidermis
• the NHEKs are prepared as in Example 5.
• the RHEs are prepared as in Example 6 (complete medium including vitamin
• the inflammatory mixture (cytokine mix, M3) consists of interleukin-17 (IL-1)
• oncostatin M (OSM) and tumor-necrosis factor alpha (TNFa), all from R & D Systems, at the final concentration of 3 ng / ml each.
• OSM oncostatin M
• TNFa tumor-necrosis factor alpha
• the reference is the "JAK inhibitor 1" (Calbiochem CAS 457081-03-7) to 10 ⁇ final.
• the extract EX10MF1046 of Example 1 is tested at 20 ⁇ g / ml, in the medium of culture of the RHE.
• the NHEK are pre-cultured as in Example 5 and then treated for 24 hours with the EX10MF1046 extract (20 ng / ml) or the JAK inhibitor (10 ⁇ l).
• the cytokine mixture is then added to the media containing or not the extract and the cultures are continued for 24 hours.
• the cell mats are rinsed and then extracted in lysis buffer; the following protocols and analyzes are the same as those of Example 5.
• the RHEs are placed at the air-liquid interface (J0) and grown to J11. Then the RHEs are treated systemically with the EX10MF1046 extract (20 ng / ml) or the JAK inhibitor (10 ⁇ l) for 7h. The cytokine mixture is added to the media containing or not the products and the cultures are continued for 48 hours.
• the tissue treatment, the markings and the analysis are carried out as in example 6. Digital images of the sections observed are recorded.
• the NHEKs or the RHEs are treated with the extract EX10MF1046 or the reference, then with a cytokine mixture consisting of at least one cytokine activating the Jak / Stat pathway, either OSM or IL-22 (activators of STAT-3/1); an activator of NF-kB pathway, either IL-1 or TNF- ⁇ and a third cytokine that may be IL-17 (CREBP activator) leading to a psoriasis-like response or IL-4 / IL-13 ( activator of STAT-6), pointing towards atopic dermatitis 5 "7.
• a cytokine mixture consisting of at least one cytokine activating the Jak / Stat pathway, either OSM or IL-22 (activators of STAT-3/1); an activator of NF-kB pathway, either IL-1 or TNF- ⁇ and a third cytokine that may be IL-17 (CREBP activator) leading to a psoriasis-
• cytokines are also more or less activators of the MAKPkinase (mitogen-activated protein kinase) pathways in the keratinocyte
• MAKPkinase mitogen-activated protein kinase
• STAT-3/1 (OSM, IL-22) 2-3, 7 are crucial in cutaneous pathophysiology, they are responsible for the effect on the cutaneous differentiation and morphological changes observed in these pathologies.
• Other cytokines notably I L-17, TNF-a and I L-1 5-7 are more involved and highly synergistically in the induction of innate immunity (antimicrobial peptides) and production of chemokines responsible for maintaining and the amplification of the inflammatory loop responsible for these chronic pathologies 5 "7 .
• This selected mixture contains the OSM as inducer of STAT-3/1, associated with TN F- ⁇ (NF- ⁇ B, MAP kinases) and I L-17 (to give the "psoriasis" orientation, Th17.
• This mixture has a highly synergistic inflammatory effect which mimics skin inflammatory pathology in the epidermis, and in particular psoriasis, by replacing L-17 (cytokine Th17) with one or more Th2 cytokines (I L-4). / I L-13) lead to a skin phenotype closest to atopic dermatitis 6. in both cases, abnormal differentiation of the epidermis is characterized with loss of terminal differentiation markers, hyperplasia (etc).
• the reference is "JAK inhibitor 1", a broad Jak-Stat inhibitor and tested in high concentration.
• the culture medium of the RHE at 48h is removed and frozen at -80 ° C.
• the content of I L-8 was assayed using a specific ELISA kit (R & D Systems DY208), according to the protocol recommended by the supplier.
• the influence of the extract EX10M F1046 at 20 ⁇ g / ml is studied on the expression of the transcripts of markers KRT1, KRT10, filaggrin and loricrin, by the cultures of keratinocytes stimulated (or not (Ctrl-) by a mixture of cytokines (I L-17, OSM, TNFa at 3 ng / ml, PSO mix)
• the treatments are 48 h in total, the analysis is carried out by RT-qPCR.
• EX10M F1046 protects the epidermis from the effects of inflammation by restoring the expression of the markers of late differentiation, filaggrin and loricrin, and that this extract induces a strong overexpression of keratin KRT1 and KRT10 under these conditions. . Extract EX10MF1046 thus potentially protects skin-induced differentiation defects caused by inflammation.
• FIG. 8 shows a partial but clear restoration of the expression of the KRT10 protein by treatment with the EX10M F1046 extract from the RHEs treated with the pro-inflammatory mixture.
• FIG. 9 shows the inhibitory effect of the extract EX10MF1046 (at 2Cg / ml) of the expression of chemokines induced by inflammation of the keratinocytes.
• This effect results from the interruption of the inflammatory loop by preventing the recruitment of leucocytes at the level of the lesional skin.
• This effect is in addition to the effects on differentiation ( Figure 7) to contribute to the return to normal homeostasis of the skin (resolution of inflammation).
• EX10M F1046 very strongly inhibits the expression / release of chemokines and in particular IL-8 at the level of the protein (FIG. 10), confirming its potential inhibitory effect on the recruitment of leukocytes (polynuclear in the case of IL-8) cutaneous lesions (in addition to the positive effect on these same lesions).
• leukocytes polynuclear in the case of IL-8
• cutaneous lesions in addition to the positive effect on these same lesions.
• EX10MF1046 therefore protects against the deleterious effects (skin lesions) of cytokines produced by leukocytes (1), while blocking the recruitment of leukocyte infiltrates and thus breaking the vicious cycle of chronic inflammation (2).
• the hair bulbs are microdissected from a facelift and placed as soon as isolated in culture medium (William E medium supplemented, I nvitrogen) containing or not (control), the test extract then incubated for 72 hours. hours. For each condition, an excess of bulbs is prepared in order to reach the target value of 6 hair / condition selected in final.
• the hair is dry frozen in liquid nitrogen and stored at -
• the extract EX10M F1046 of Example 1 is tested at 20 ⁇ g / ml, in the medium of culture of the RHE.
• RNA amplification and synthesis of biotinylated RNA analogues are performed using the "GeneChip 3'IVT Express" kit (Affymetrix ® ).
• Hybridization and labeling are carried out using the kit “GeneAtlas TM hybridization, wash and stain kit for 3'IVT arrays” (Affymetrix).
• Hybridization of the fragmented RNAa on the Affymetrix ® HG-U219 chip is performed on the GeneAtlas TM fluidics station (Affymetrix) for 20 hours at 45 ° C. All experimental and standardization procedures are performed according to the supplier's instructions.
• the analysis is performed by microarray full transcriptome on chip Affymetrix 0 HG-
• Keratin is a major component of the hair shaft. An increase in these keratins will potentially have a positive impact on hair development / strengthening.
• Boniface K Bernard FX, Garcia M, Gurney AL, Lecron JC, Morel F. IL-22 inhibited epidermal differentiation and induced proinflammatory gene expression and migration of human keratinocytes. J Immunol. 2005 Mar 15; 174 (6): 3695-702.) Boniface K, Div C, Morel F, Pedretti N, Froger J, Ravon E, Garcia M, Venereau E, Preisser L, Guignouard E, Guillet G, Dagregorio G, Pole J, Moles JP, Yssel H,
• Oncostatin M secreted by skin infiltrating T lymphocytes is a potent keratinocyte activator involved in skin inflammation. J Immunol. 2007 Apr. 178 (7): 4615-22.

Priority Applications (4)

Applications Claiming Priority (4)

Publications (2)

Family

ID=52823666

Family Applications (1)

Country Status (5)

Cited By (3)

Families Citing this family (6)

Citations (1)

Family Cites Families (15)

• 2015
  • 2015-03-18 US US15/127,102 patent/US20170112737A1/en not_active Abandoned
  • 2015-03-18 EP EP15715346.1A patent/EP3119382B1/fr active Active
  • 2015-03-18 KR KR1020167028671A patent/KR20160127137A/ko not_active Application Discontinuation
  • 2015-03-18 WO PCT/FR2015/050664 patent/WO2015140470A2/fr active Application Filing
  • 2015-03-18 CN CN201580014439.2A patent/CN106456478A/zh active Pending

Patent Citations (1)

Non-Patent Citations (6)

Also Published As

Similar Documents

Legal Events